In healthy individuals, the level of platelets and other blood cells is maintained in a narrow band by an active feedback mechanism that balances the rate of production with that of loss due to peripheral consumption and clearance. Certain disorders such as bone marrow hypoplasia or acute myelogenous leukemia depress the rate of production, while other conditions, such as certain viral infections, or alloimmunization following exposure to foreign antigens, during pregnancy or as a result of blood transfusion, contribute to accelerated clearance.
In addition, chemotherapy, for patients with hematologic malignancies, impairs or completely suppresses the production of platelets from megakaryocytes (HarkerFinch1969), and even with finite residual production, platelet function in such patients may be impaired. Thus, Psaila2012 reports reduced expression levels of membrane glycoproteins including GPIb which binds to von Willebrand factor on (sub-)endothelial cells at sites of vascular injury (“lesions”) and thereby mediates platelet adsorption.
Hemorrhages of varying degree of severity remain a principal factor contributing to morbidity and mortality of patients receiving chemotherapy for hematologic malignancies, including bone marrow transplant candidates. While low platelet count per se may not be the cause of bleeding, it may exacerbate the risk of an insufficient response in the event (HoTin-Noe2011, Loria2013). Under current treatment guidelines (Slichter2005), patients receiving chemotherapy are managed in accordance with “one-size-fits-all” algorithms including triggers for prophylactic platelet transfusion. Many clinical studies over the past decade or more have sought to identify an “optimal” value for such a trigger, often by looking for a significant increase in frequency and severity of bleeding episodes at lower platelet count (Estcourt2012). At present, only “bleeds” causing visible symptoms (including petechiae, bruises or external blood loss) are routinely monitored or assessed during treatment, and changes in transfusion trigger, while often based on bleeding episodes, may not be correlated to the trigger levels, or changes thereof seSee, -Rioux-Masse B, Laroche V, Bowman R J et al. The influence of bleeding on trigger changes for platelet transfusion in patients with chemotherapy-induce thrombocytopenia Transfusion. 2013 February; 53(2):306-14.
However, inflammation, has been has been recently shown to cause of bleeding by impairing vascular integrity (Ho-Tin-Noe2011), and platelets have been shown to be “vital in maintaining vascular integrity (Nachman2008), especially in inflamed tissue (Goerge2008) This is a concern for patients receiving chemotherapy who frequently present with symptoms of inflammation, ranging from fever to sepsis.
Recent work indicates a role of platelets, beyond that of maintaining hemostasis, in modulating inflammatory reactions and immune responses by direct interaction with leukocytes and epithelial cells and by releasing inflammatory mediators (Assinger2014). In fact, transfusions themselves are known to be associated with an increased risk of infection as well as inflammation, where the latter may be caused or exacerbated by chemotherapy (vanderMost2008) and by hemolytic transfusion reactions (Strobel2008). Moreover, it has been observed, in a mouse model, that severe platelet deprivation leads to splenic necrosis, with deleterious effects on innate and adaptive immune responses to certain infectious agents (Loria2013).
Thus, individual requirements for maintaining vascular integrity may change over time, and may differ between patients, in a manner reflecting inflammatory and perhaps other clinical conditions.
Accordingly, a method is needed to determine individual transfusion regimens, especially for severely thrombocytopenic patients, by assessing the individual (and possibly time-varying) need for support in relation to the condition of the patient, by assessing that condition, non-invasively and continually, and determining the requirement for maintaining an adequate level of platelets in circulation to ensure a protective immune response, and satisfying the demand for platelets in maintaining vascular integrity. To ensure adequate quantities of antigen-profiled platelets are available to needy patients, and to reduce cost, the method should avoid excess utilization of platelets (and related services), such as the administration of any particular antigen-profiled platelets. The method may also ensure that patients who may have developed allo-antibodies to platelets are administered sufficient quantities of platelets of the correct type to ensure a protective immune response, and maintain vascular integrity.